P1211: CLINICAL HETEROGENEITY OF HIGH-GRADE B-CELL LYMPHOMA. EDGE OF TRANSFORMATION.
Authors: A. Misyurina, S. Kravchenko, A. Magomedova, A. Kovrigina, T. Obukhova, K. Sychevskaya, E. Zakharko, E. Rubkina, V. Misyurin, F. Babaeva
Journal: HemaSphere (2022)

Background: In the revised version of WHO classification of 2017th the group of high-grade B-cell lymphoma double-hit (HGBL DH) was distinguished from high-grade B-cell lymphoma not otherwise specified (HGBL NOS) based on revealing of rearrangements of genes c-MYC and BCL2 and/or BCL6. Nowadays we have more data telling us that these provisional entities are represented by different types of lymphomas which can develop from low-grade: follicular (FL) or marginal zone lymphoma (MZL). Aims: To show heterogeneity of HGBLs based on clinical features and to distinguish the group of transformed low-grade-lymphomas (LGLs) from de novo HGBLs. Methods: We have analyzed the data of 99 patients (pts) with HGBLs that have been treated since 2010 till 2022 years. Six pts had HGBL TH, 26 pts - c-MYC/BCL2 HGBL DH, 16 pts - c-MYC/BCL6 HGBL DH and 51 pts - HGBL NOS. The diagnosis was confirmed by histological and immunohistochemical study in all cases. FISH was performed in all pts to reveal translocation of genes c-MYC (8q24), BCL2 (18q21) and BCL6 (3q27). We suggested an integral transformation index (ITI) indicating the probability of HGBL development from LGL (FL or MZL). It included following: histologically confirmed transformation (by two consequent biopsies or morphological signs of high- and low-grade lymphomas in one biopsy sample), lymphoma history longer than 4 months, discordant bone marrow involvement (infiltration by small B-cells), paraprotein secretion, leukemic blood count, submitted by flow cytometry. Compassion of groups was carried out using χ2 test. Differences were considered as significant at p-value < 0,05 (STATISTICA 12.0). Results: Morphological signs of transformation from LGL were revealed: in 3/6 (50%) of pts with HGBL TH (from FL); in 11/26 (42%) of pts with c-MYC/BCL2 HGBL DH (from FL), in 6/16 (38%) of pts with c-MYC/BCL6 HGBL DH (from MZL) and in 4/51 (8%) of pts with HGBL NOS (1 – from FL, 3 - from MZL). When we estimated all HGBL pts regarding on ITI we revealed that: 34/51 (67%) of pts with HGBL NOS, 16/26 (62%) of pts with c-MYC/BCL2 HGBL DH, 13/16 (81%) of pts with c-MYC/BCL6 HGBL DH and 5/6 (83%) of pts with HGBL TH had at least one sign of transformation. ITI significantly increased the probability to reveal the transformation from LGL in pts with c-MYC/BCL6 HGBL DH (p=0,01) and HGBL NOS (p<0,001) compared with morphological study only. We hadn’t observed paraprotein secretion in group of pts with c-MYC/BCL2 HGBL DH or HGBL TH that could highlight pathogenic differences between c-MYC/BCL2 HCBL DH and HGBL TH from c-MYC/BCL6 HGBL DH and HGBL NOS. Furthermore, groups of patients with c-MYC/BCL2 HGBL DH and HGBL TH were predominantly presented by GCB-subtype (93%) while c-MYC/BCL6 HGBL DH – by non-GCB (44%), (p=0,03). We found a strong correlation between CNS involvement (at the time of disease onset or in relapse/progression) and having ITI score at least 1 point (from 1 to 4), (p=0,008). Summary/Conclusion: We suggested a powerful Integral Transformation Index to distinguish cases of low-grade lymphomas transformation into high-grade. c-MYC/BCL2 HGBL DH and HGBL TH are more homogenous group of GCB-lymphomas in majority of cases represented by transformation of FL. C-MYC/BCL6 HGBL DH and HGBL NOS are more heterogenous and in some cases can be represented by transformation of MZL with paraprotein secretion. Cases of transformed FL without c-MYC rearrangements also can be involved into HGBL NOS basket. Involvement of the CNS is predominantly characteristic of transformed low-grade lymphomas.